Many drugs and other chemicals that are ingested by man are metabolized to reactive intermediates that bind to tissue macromolecules and ultimately produce tissue lesions. Because these metabolites are very reactive, we are developing indirect methods for elucidating their structures. These methods involve trapping the intermediates formed in microsomal incubations with cysteine or gluathione, chromatographic isolation of the glutathione and cysteine conjugates, and structure elucidation of the purified conjugates using mass spectrometry and nmr spectroscopy. The techniques have been successfully applied to various hydrazines, alpha-methyldopa and 2-hydroxyestradiol. Other compounds which form reactive intermediates such as the furans and furan drug, furosemide, and analgesic drugs, acetaminophen and phenacetin, are presently being investigated.